More than 90% of adults are latently infected throughout their lifetime with the ubiquitous herpesvirus Epstein-Barr virus (EBV). While EBV infection is usually asymptomatic during childhood, it is estimated that half of first-time infected adolescents or adults develop infectious mononucleosis, a disease characterized by polyclonal B cell activation and massive expansion of T cells. EBV is an oncogenic virus; it is associated with Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma. At least 1% of organ and bone marrow transplant recipients develop EBV+ lymphomas; and EBV lymphoproliferative disorders are common in AIDS patients. The tumors are often associated with vast T cell infiltrates. The SCID/hu mouse is well accepted as an animal model for EBV lymphomagenesis, because SCID mice adoptively transferred with EBV seropositive PBMC from healthy human donors develop EBV+ B cell lymphomas at a high rate. These tumors are strictly T cell dependent and can be prevented by blocking the B-T interaction. We have recently established that EBV transactivates a human endogenous retrovirus, HERV-K18, that encodes a superantigen, which strongly activates T cells. This is the first described report of a pathogen inducing a host cell superantigen. We propose that HERV-K18 Env superantigen activated T cells contribute to EBV lymphomagenesis. This proposal seeks to test whether blocking the superantigen driven T cell response prevents tumorigenesis in the SCID/hu lymphoma mouse model. We propose to block T cell activation by: I. developing monoclonal antibodies specific for the HERV-K18 superantigen; II. blocking CD28/ICOS costimulation; III. induction of T cell anergy; and IV. ligation of immuno-inhibitory receptor PD-1. Since several other herpesviruses are associated with superantigen or superantigen-like activity, these experiments may have broad-reaching implications for herpesvirus biology. Overall, these studies represent a completely new approach towards understanding the potential role of T cells in herpesvirus oncogenesis. [unreadable] [unreadable]